Systemic delivery of pharmacologically active agents, including by inhalation parenteral, topical, or transdermal delivery or by ingestion, is an effective and easily managed mode of administration, but is less than adequate for some treatment applications. For example, some pharmacologically active agents are poorly absorbed from the blood stream, or alternatively, irritate the stomach lining. Thus, in some instances, local delivery of pharmacologically active agents is desirable.
Local delivery of pharmacologically active agents to peripheral nerves is often times desirable for the management of acute and chronic pain. However, local delivery of pharmacologically active agents to peripheral nerves is currently primarily performed by bolus injections or by the insertion of an infusion catheter. For example, bupivacaine infusion has been used to alleviate pain at iliac crest donor sites (Wilkes R A. and Thomas W G. (1994) Journal of Bone & Joint Surgery—British Volume. 76(3):503). Chronic epidural bupivacaine-opioid infusion has also been used to treat intractable cancer pain (Du Pen S L. et al., Pain (1992) 51(2):263-4).
The treatment of chronic osteomyelitis includes systemic antibiotics. However, the delivery of antibiotics to bone varies considerably. Oral antibiotics are unpredictable for this use, effect relatively low levels of bone, and are infrequently used. Intravenous antibiotics are used commonly in the treatment of chronic osteomyelitis, but six weeks of intravenous antibiotics is necessary for adequate therapy. Even with prolonged intravenous antibiotics, there is a significant relapse rate.
Although bolus injections and infusions are generally a safe and efficacious form of treatment, this mode of local delivery can be limited by the volume of liquid that can be injected, the maximal non-toxic concentration of the pharmacologically active agent that can be administered, and the system toxicity levels that can ensue subsequent to absorption and circulation to other body organs. In addition, bolus infusions are not always effective. For example, in one study intra-articular bupivacaine (up to 0.5%) at a rate of 4 mL/hr following primary total knee arthroplasty neither reduced morphine requirements nor decreased subjective pain scores during the first 24 hours after surgery. The lack of effective pain control with intra-articular bupivacaine infusion was speculated to result from the difficulty in providing effective local anesthetic effect in the relatively large intra-articular space without drug overdose. One patient in the reported study receiving 0.5% intra-articular bupivacaine at 4 mL/hr had a serum bupivacaine level of 1.2 μg/mL, in excess of the 1.0 μg/mL value at which toxicity has been reported (Journal of Orthopaedic Surgery(2002) 10(1): 53-60).
Furthermore, if administered by infusion catheter, bolus delivery requires monitoring to initially place the catheter, and continually thereafter to ensure that the catheter does not migrate. This mode of local delivery is also suboptimal. Thus, alternative methods of localized drug delivery would be desirable.
In efforts to address this need, many implantable drug delivery devices have been developed over the past several years. Such drug delivery devices may be formulated from synthetic or natural, biodegradable or non-biodegradable, polymers. Biodegradable polymers are preferred since these materials gradually degrade in vivo over time, e.g., by enzymatic or non-enzymatic hydrolysis, when placed in an aqueous, physiological environment. Thus, the use of biodegradable polymers in drug delivery devices is preferred since their use avoids the necessary removal of the drug delivery device at the end of the drug release period.
The drug is generally incorporated into the polymeric composition and formed into the desired shape outside the body. This solid implant is then typically inserted into the body of a human, animal, bird, and the like through an incision. Alternatively, small discrete particles composed of these polymers can be injected into the body by a syringe.
Certain formulations of these polymers also can be injected via syringe as a liquid polymeric composition. These compositions are administered to the body in a liquid state or, alternatively, as a solution with solid microparticles of polymer dispersed therein. Once in the body, the composition coagulates into a solid. One type of polymeric composition includes a nonreactive thermoplastic polymer or copolymer dissolved in a body fluid-dispersible solvent. This polymeric solution is placed into the body where the polymer congeals or precipitatively solidifies upon dissipation or diffusion of the solvent into the surrounding body tissues.
Non-toxic hydrogel-forming polymeric materials, which are capable of absorbing a substantial amount of water to form elastic or inelastic gels, also have been used in the formulation of drug delivery devices. See, e.g., Lee, J. (1985) Controlled Release 2: 277. Drug delivery devices incorporating hydrogel-forming polymers offer the flexibility of being implantable in liquid or gelled form. Once implanted, the hydrogel forming polymer absorbs water and swells. The release of a pharmacologically active agent incorporated into the device takes place through this gelled matrix via a diffusion mechanism.
However, many hydrogels, although biocompatible, are not biodegradable. Furthermore, drug delivery devices comprising hydrogels may require the use of undesirable organic solvents for their manufacture. Residual amounts of such solvents could potentially remain in the drug delivery device, where they could cause solvent-induced toxicity in surrounding tissues or cause structural or pharmacological degradation to the pharmacologically active agents incorporated within the drug delivery device.
In particular, nonbiodegradable polymer implants, most commonly various derivatives and co-polymers of poly(methylmethacrylate) and poly(N-alkyl acrylamide), have been used for local delivery of antibiotics, such as Tobramycin, gentamicin, and vancomycin. A biodegradable antibiotic implant made of polylactic acid and poly(DL-lactide):co-glycolide combined with vancomycin has been developed and evaluated in a localized osteomyelitic rabbit model (Cahoun J H et al. Clinical Orthopaedics & Related Research. Current Trends in the Management of Disorders of the Joints. (1997) 341:206-214). More recently the GLIADEL® wafer (Guilford Pharmaceutical Corp, Baltimore, Md.), which was FDA-approved for implant in post surgical treatment of certain kinds of brain tumors, is used to deliver an oncolytic agent, carmustine, from a wafer of a biodegradable polyanhydride copolymer. Local drug delivery from implants provides the advantage of high tissue concentrations with relatively low serum levels, thereby avoiding some of the toxicity associated with systemic delivery. Bioactive agent-impregnated polymer implants are particularly attractive because they not only deliver high tissue levels of antibiotic or oncolytic agent, but also help fill the dead space that occurs after certain surgeries.
However, drug release characteristics of such implanted drug delivery devices may be suboptimal. Many times, the release of pharmacologically active agents from an implanted drug delivery device is irregular. There is an initial burst period when the drug is released primarily from the surface of the device, followed by a second period during which little or no drug is released, and a third period during which most of the remainder of the drug is released at a substantially lower rate than in the initial burst.
Thus, despite advancements in the art, new and better drug delivery devices are needed for sustained, controlled local delivery of pharmacologically active agents that are also biodegradable and biocompatible, as well as resorbable such that removal of the device is not necessary.